The protein phosphorylation/dephosphorylation cycle is one of the major regulatory mechanisms employed by eukaryotic cells to control cellular activities. It is estimated that more than 10% of the active proteins in a typical mammalian cell are phosphorylated. During protein phosphorylation/dephosphorylation, phosphate groups are transferred from adenosine triphosphate molecules to a protein by protein kinases and are removed from a protein by protein phosphatases.
Protein phosphatases function in cellular signaling events that regulate cell proliferation and differentiation, cell-to-cell contacts, the cell cycle, and oncogenesis. Three evolutionary distinct protein phosphatase families have been identified. These include the serine/threonine phosphatases, the protein tyrosine phosphatases, and the acid/alkaline phosphatases (Carbonneau H. and Tonks N. K. (1992) Annu. Rev. Cell Biol. 8:463-93).
Phosphatidic acid phosphate (PAP) is metabolized to diacylglycerol in the classical pathway of glycerolipid biosynthesis by dephosphorylating phosphatidic acid. Phosphatidic acid and its metabolic derivative, lysophosphatidic acid, are known to be potent mitogens and activators when exogenously added to different cells. Two isoforms of PAP exist in rat liver. The first, designated PAP1, is associated with the cytosol and microsomes, and appears to be responsible for glycerolipid biosynthesis. The second isoform PAP2 is bound to the plasma membrane and is involved in cellular signal transduction. The activities of the two PAP isoforms appear to undergo different activity alterations in several liver diseases (Day, C. P (1993) Clin. Sci. (Lond.) 85:281-287).
Phospholipase D (PLD) is activated in a variety of cells by hormones and growth factors. Activated PLD results in the generation of phosphatidic acid (PA) by hydrolysis of PAP, which can be further metabolized by PA phosphohydrolase to diacylglycerol (DG). The generation of PA by PLD in neutrofils has been linked to the activation of the respiratory burst enzyme, NADPH oxidase. During phosphorylation-dependent oxidase activation, PA, but not DG, induces phosphorylation of a wide range of proteins, the most prominent of which is the NADPH oxidase component p47-phox (phagocytic oxidase component). The absence of p47-phox is implicated in a genetic defect called p47-phox-deficient chronic granulomatous disease (P47-GCD). P-47-GCD is caused by a GT deletion at the beginning of exon 2. The GT deletion has been found in 11 becteriophage and 15 YAC clones.
The discovery of two new human protein phosphatases and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of immune disorders and diseases associated with cancer.